1. Field of the Invention
The present invention relates in general to detection of changes in viscosity of a fluid and, more particularly, to detection of changes in viscosity of blood that has been treated with viscosity-altering substances.
2. Statement of the Problem
The ability to detect changes in viscosity of fluids such as blood, food products, and various other liquid compositions (e.g., industrial fluids, oil production fluids, etc.) can have immense practical value. For example, the ability to detect changes in viscosity of human blood resulting from blood coagulation can have tremendous consequences since the balance between normal hemostasis and coagulation or anticoagulation is essential in maintaining the integrity of the circulatory system and in stopping both external and internal bleeding. However, it is sometimes necessary to modify the natural coagulation system, either by increasing or by decreasing the rate of blood coagulation. For example, during open heart surgery, a patient must often be supported by a heart/lung bypass machine that provides extracorporeal blood circulation while the heart is stopped. To prevent blood from clotting upon exposure to the bypass apparatus, the patient is treated with high doses of heparin, a naturally occurring substance that significantly prolongs the clotting time of blood. When the time comes to remove the patient from the heart/lung bypass machine, however, it is desirable for the patient's blood to regain its normal coagulation characteristics so that it will again be able to clot and assist in healing incisions and stopping internal or external bleeding. This reversal of the effects of heparin is achieved by treating the patient's blood with an anticoagulant-reversing substance, such as protamine, capable of neutralizing heparin or other anticoagulating substances.
To successfully maintain anticoagulation during a surgical procedure and neutralize the heparin at the conclusion of surgery, it is necessary to determine the concentration of heparin in the patient's blood. It is extremely important during surgery that this determination be made quickly and accurately using a minimal blood sample. Since the activity of heparin varies from batch to batch and patient to patient, this determination cannot be made on the basis of the amount of heparin administered. Protamine also varies in potency from batch to batch and from patient to patient. Allergic responses to protamine also have been reported. Furthermore, protamine itself acts as an anticoagulant. Thus, for optimal reversal of heparin action, it is essential to use only that amount of protamine that will directly neutralize the amount of active heparin in the blood being circulated.
In addition to preventing coagulation of blood during heart/lung bypass surgery, it is often desirable to lower the tendency of blood to coagulate on a long-term basis. Long-term anticoagulant treatment has applications for preventing strokes, pulmonary embolisms, and thromboses, for hemodialysis, and for treatment after acute myocardial infarction. Such long-term treatments do however require lower dosages of anticoagulant compared to those used during surgical procedures. Long-term treatments also require the clotting time of blood to be confined within a narrower range.
In view of the varying activities of anticoagulants such as heparin and the varying responses of patients to anticoagulants, it is essential to monitor anticoagulant therapy closely. Dose-response tests measure changes in clotting time in response to differing doses of anticoagulant in order to determine the correct dose of anticoagulant for a particular patient. Clotting time or activated clotting time tests are used to determine whether the blood has achieved the desired level of anticoagulation. Heparin/protamine (anticoagulant/neutralizer) titrations provide a quantitative determination of heparin (anticoagulant) levels. Such tests are based on measuring the time necessary for the blood to coagulate.
Many methods have been developed to measure changes in the viscosity of fluids, including measuring the coagulation time of blood as an empirical measure of blood viscosity. Manual methods for accomplishing clotting time tests are well known to this art. However, these manual methods require relatively long times and large fluid samples and are subject to variable results and inaccuracies due to operator variances. As a result, it is desirable to provide methods and apparatus to automate these tests in order to provide quick, consistently accurate analytical tests. The following patents describe a variety of such apparatus and methods.
U.S. Pat. Nos. 3,635,678 and 3,967,934 to Seitz et at. describe an apparatus for determining changes in viscosity of a fluid held within a test tube. A steel ball is held at a certain location in the test tube by a magnet while the tube moves up and down. When the fluid in the tube clots, the steel ball changes position relative to the magnet, and this change in position is detected photoelectrically.
U.S. Pat. No. Re. 27,866 to Adler depicts an apparatus in which the coagulation of a blood plasma sample is intensified by dispersing iron oxide particles throughout the sample and then subjecting the particle-sample mixture to a rotating magnetic field that causes the particles to move within the sample and activate the clotting reaction. When the fluid produces fibrin strands, the moving particles collect these strands, changing the optical properties of the particle-sample mixture. The change in optical properties is detected by light-sensitive means.
U.S. Pat. Nos. 3,836,333 and 5,145,082 to Mintz describe a blood coagulation detection apparatus in which a blood sample is placed in a test tube with a ferromagnetic member. The test tube is then rotated about its axis, producing a relative motion between the tube and the ferromagnetic member; that is, as the tube rotates, the ferromagnetic member remains in the same predetermined position within the tube. When the blood in the tube clots, the ferromagnetic member is displaced from this predetermined position, and movement of the member is sensed magnetically with a reed switch.
Cooper et al. (U.S. Pat. No. 4,599,219) and Jackson et at. (U.S. Pat. No. 4,752,449) each describe an apparatus and method in which a plunger assembly is repeatedly raised and released so that it descends through a sample of fluid contained within a tubular cartridge. The cartridge includes an upper chamber in which the fluid sample is injected via syringe and a lower chamber containing any desired viscosity-altering substances, and means to seal the upper chamber and communicate the contents of the lower chamber to the upper chamber. The plunger is raised mechanically, and its position is sensed by an optical detector. When the viscosity of the fluid sample increases, the plunger will descend more slowly through the fluid sample.
U.S. Pat. No. 4,648,262 to Reis et al. describes a viscometer in which the fluid sample whose viscosity is to be measured is placed in a capillary tube along with a metal ball. A magnet mounted on a rotating drum periodically raises the ball to the top of the tube and then releases the ball to fall to the bottom of the tube. The viscosity of the fluid is determined by the rate of descent of the ball in the tube.
U.S. Pat. No. 4,879,432 to Vieillard provides a method and apparatus to measure coagulation of blood in which a stream of solid particles is established in a tube containing the blood and the time at which the stream of particles is stopped marks the coagulation of the blood. The particles are micron-sized grains of, for example, glass, that are highly wettable so that they travel down the tube under the effect of gravity. Their small size means that they are immediately stopped by the fibrin network as soon as coagulation has begun. Photoelectric cells detect the stopping of the particles.
U.S. Pat. Nos. 5,302,348 and 5,372,946 to Cusack et at. describe a cuvette used for performing a coagulation time test on blood. The blood is deposited into a fluid reservoir on a disposable cuvette. The blood is then drawn by a machine from the reservoir into a capillary conduit within the cuvette. The capillary conduit has a narrower region at one point along its length. The machine causes the blood in the conduit to move back and forth, traversing the narrow region. The time the blood requires to traverse the narrow region of the conduit is measured during each iteration. When this traversal time increases by a predetermined amount over the immediately preceding time, the blood is considered to have coagulated.
Various problems and drawbacks exist with these previous methods and apparatus for automating fluid viscosity determinations. Some of these problems are particularly noteworthy in the realm of surgery. For example, nearly all the methods described above require large samples that are manually obtained and manually metered into the apparatus, thereby exposing the operator to contact with the blood as well as introducing operator error and/or inconsistencies when measuring the volume of the test sample. Moreover, most of these methods allow only one test chamber to be measured at a time. In effect, this one test chamber approach prevents analyses, such as heparin/protamine titration, that require simultaneous testing in multiple chambers. The previous methods and apparatus also are limited in allowing only one type of test to be run per chamber or cartridge, and many have a very limited test menu. It should also be noted that many of these prior art apparatus are complicated to use and are not readily adaptable to use in a surgical environment. Moreover, the test results from many of these prior art apparatus do not reliably relate to the test results available from recognized and accepted, albeit slow, manual analytical laboratory techniques. Hence, many physicians do not consider such automated devices to be reliable.
It would therefore be desirable to have the ability to conduct multiple viscosity-related analytical tests quickly, reliably, and reproducibly during surgical and clinical procedures. It would also be desirable if such tests could be carded out by an automated apparatus that is easy to use and not subject to variability introduced by operator inconsistencies. It also is highly desirable that the disposable elements of an apparatus used to carry out such tests be self-contained, inexpensive, and capable of withstanding reasonable storage periods under a variety of conditions.